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Pharmacokinetics and Pharmacodynamics of Antifungals in Children and their Clinical Implications

Clinical Pharmacokinetics volume 53, pages 429–454 (2014)Cite this article

Abstract

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.

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References

  1. Blyth CC, Palasanthiran P, O’Brien TA. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics. 2007;119(4):772–84.

    PubMed  Google Scholar 

  2. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(2 Pt 1):285–91.

    PubMed  Google Scholar 

  3. Benjamin DK, DeLong E, Cotten CM, Garges HP, Steinbach WJ, Clark RH. Mortality following blood culture in premature infants: increased with Gram-negative bacteremia and candidemia, but not Gram-positive bacteremia. J Perinatol. 2004;24(3):175–80.

    PubMed  Google Scholar 

  4. Saiman L, Ludington E, Pfaller M, Rangel-Frausto S, Wiblin RT, Dawson J, et al. Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey Study Group. Pediatr Infect Dis J. 2000;19(4):319–24.

    PubMed  CAS  Google Scholar 

  5. Walmsley S, Devi S, King S, Schneider R, Richardson S, Ford-Jones L. Invasive Aspergillus infections in a pediatric hospital: a ten-year review. Pediatr Infect Dis J. 1993;12(8):673–82.

    PubMed  CAS  Google Scholar 

  6. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32(3):358–66.

    PubMed  CAS  Google Scholar 

  7. Dodds Ashley ES, Lewis R, Lewis JS, Martin C, Andes D. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006;43(Suppl 1):S28–39.

    CAS  Google Scholar 

  8. Steinbach WJ. Antifungal agents in children. Pediatric Clin N Am. 2005;52(3):895–915, viii.

    Google Scholar 

  9. Geber A, Hitchcock CA, Swartz JE, Pullen FS, Marsden KE, Kwon-Chung KJ, et al. Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility. Antimicrob Agents Chemother. 1995;39(12):2708–17.

    PubMed Central  PubMed  CAS  Google Scholar 

  10. Polak A, Scholer HJ. Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy. 1975;21(3–4):113–30.

    PubMed  CAS  Google Scholar 

  11. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362(9390):1142–51.

    PubMed  CAS  Google Scholar 

  12. Andes D, van Ogtrop M. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob Agents Chemother. 2000;44(4):938–42.

    PubMed Central  PubMed  CAS  Google Scholar 

  13. Louie A, Drusano GL, Banerjee P, Liu QF, Liu W, Kaw P, et al. Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother. 1998;42(5):1105–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  14. Andes D, van Ogtrop M. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother. 1999;43(9):2116–20.

    PubMed Central  PubMed  CAS  Google Scholar 

  15. Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother. 2001;45(3):922–6.

    PubMed Central  PubMed  CAS  Google Scholar 

  16. Manavathu EK, Ramesh MS, Baskaran I, Ganesan LT, Chandrasekar PH. A comparative study of the post-antifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans. J Antimicrob Chemother. 2004;53(2):386–9.

    PubMed  CAS  Google Scholar 

  17. Chryssanthou E, Sjolin J. Post-antifungal effect of amphotericin B and voriconazole against Aspergillus fumigatus analysed by an automated method based on fungal CO2 production: dependence on exposure time and drug concentration. J Antimicrob Chemother. 2004;54(5):940–3.

    PubMed  CAS  Google Scholar 

  18. Andes D, Diekema DJ, Pfaller MA, Prince RA, Marchillo K, Ashbeck J, et al. In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model. Antimicrob Agents Chemother. 2008;52(2):539–50.

    PubMed Central  PubMed  CAS  Google Scholar 

  19. Andes DR, Diekema DJ, Pfaller MA, Marchillo K, Bohrmueller J. In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother. 2008;52(10):3497–503.

    PubMed Central  PubMed  CAS  Google Scholar 

  20. Andes D, Lepak A, Nett J, Lincoln L, Marchillo K. In vivo fluconazole pharmacodynamics and resistance development in a previously susceptible Candida albicans population examined by microbiologic and transcriptional profiling. Antimicrob Agents Chemother. 2006;50(7):2384–94.

    PubMed Central  PubMed  CAS  Google Scholar 

  21. Andes D, Marchillo K, Stamstad T, Conklin R. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother. 2003;47(10):3165–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  22. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1–10; quiz 1–2.

    Google Scholar 

  23. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996;15(3):255–9.

    PubMed  CAS  Google Scholar 

  24. Andes D. In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis. Antimicrob Agents Chemother. 2003;47(4):1179–86.

    PubMed Central  PubMed  CAS  Google Scholar 

  25. Wiederhold NP, Herrera LA. Caspofungin for the treatment of immunocompromised and severely ill children and neonates with invasive fungal infections. Clin Med Insights Pediatr. 2012;6:19–31.

    PubMed Central  PubMed  Google Scholar 

  26. Katragkou A, Roilides E. Best practice in treating infants and children with proven, probable or suspected invasive fungal infections. Curr Opin Infect Dis. 2011;24(3):225–9.

    PubMed  CAS  Google Scholar 

  27. Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49(11):4536–45.

    PubMed Central  PubMed  CAS  Google Scholar 

  28. Seibel NL, Schwartz C, Arrieta A, Flynn P, Shad A, Albano E, et al. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005;49(8):3317–24.

    PubMed Central  PubMed  CAS  Google Scholar 

  29. van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39(10):1407–16.

    PubMed  Google Scholar 

  30. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391–402.

    PubMed  CAS  Google Scholar 

  31. Hope WW, Seibel NL, Schwartz CL, Arrieta A, Flynn P, Shad A, et al. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother. 2007;51(10):3714–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  32. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.

    PubMed  CAS  Google Scholar 

  33. Groll AH, Tragiannidis A. Update on antifungal agents for paediatric patients. Clin Microbiol Infect. 2010;16(9):1343–53.

    PubMed  CAS  Google Scholar 

  34. Walsh TJ. Management of immunocompromised patients with evidence of an invasive mycosis. Hematol Oncol Clin North Am. 1993;7(5):1003–26.

    PubMed  CAS  Google Scholar 

  35. Sarosi GA. Amphotericin B. Still the ‘gold standard’ for antifungal therapy. Postgrad Med. 1990;88(1):151–2, 5–61, 65–6.

    Google Scholar 

  36. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990;12(2):308–29.

    PubMed  CAS  Google Scholar 

  37. Cohen-Wolkowiez M, Moran C, Benjamin DK Jr, Smith PB. Pediatric antifungal agents. Curr Opin Infect Dis. 2009;22(6):553–8.

    PubMed Central  PubMed  Google Scholar 

  38. Je B. Antifungal agents. In: Hardman GELL, editor. Goodman and Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 1295–312.

    Google Scholar 

  39. Dupont B. Overview of the lipid formulations of amphotericin B. J Antimicrob Chemother. 2002;49(Suppl 1):31–6.

    PubMed  CAS  Google Scholar 

  40. Vogelsinger H, Weiler S, Djanani A, Kountchev J, Bellmann-Weiler R, Wiedermann CJ, et al. Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J Antimicrob Chemother. 2006;57(6):1153–60.

    PubMed  CAS  Google Scholar 

  41. Atkinson AJ Jr, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother. 1978;13(2):271–6.

    PubMed Central  PubMed  Google Scholar 

  42. Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr. 1990;116(5):791–7.

    PubMed  CAS  Google Scholar 

  43. Benson JM, Nahata MC. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother. 1989;33(11):1989–93.

    PubMed Central  PubMed  CAS  Google Scholar 

  44. Raasch RH, Hopfer RL. Antifungal agents. In: Munson PL, Mueller RA, Breese GR, editors. Principles of pharmacology: basic concepts and clinical applications, revised reprint. New York: Chapman and Hall; 1996. p. 1401–11.

  45. Goodwin SD, Cleary JD, Walawander CA, Taylor JW, Grasela TH Jr. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin Infect Dis. 1995;20(4):755–61.

    PubMed  CAS  Google Scholar 

  46. Wingard JR, Kubilis P, Lee L, Yee G, White M, Walshe L, et al. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis. 1999;29(6):1402–7.

    PubMed  CAS  Google Scholar 

  47. Chabot GG, Pazdur R, Valeriote FA, Baker LH. Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients. J Pharm Sci. 1989;78(4):307–10.

    PubMed  CAS  Google Scholar 

  48. Furrer K, Schaffner A, Vavricka SR, Halter J, Imhof A, Schanz U. Nephrotoxicity of cyclosporine A and amphotericin B-deoxycholate as continuous infusion in allogenic stem cell transplantation. Swiss Med Wkly. 2002;132(23–24):316–20.

    PubMed  CAS  Google Scholar 

  49. Imhof A, Walter RB, Schaffner A. Continuous infusion of escalated doses of amphotericin B deoxycholate: an open-label observational study. Clin Infect Dis. 2003;36(8):943–51.

    PubMed  CAS  Google Scholar 

  50. Peleg AY, Woods ML. Continuous and 4 h infusion of amphotericin B: a comparative study involving high-risk haematology patients. J Antimicrob Chemother. 2004;54(4):803–8.

    PubMed  CAS  Google Scholar 

  51. Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ. 2001;322(7286):579–82.

    PubMed Central  PubMed  CAS  Google Scholar 

  52. Bekersky IFR, Dressler DE, et al. Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother. 2003;46:834–40.

    Google Scholar 

  53. Lewis RE, Wiederhold NP, Prince RA, Kontoyiannis DP. In vitro pharmacodynamics of rapid versus continuous infusion of amphotericin B deoxycholate against Candida species in the presence of human serum albumin. J Antimicrob Chemother. 2006;57(2):288–93.

    PubMed  CAS  Google Scholar 

  54. Janoff ASPW, Saleton SL, Swenson CE. Amphotericin B lipid complex (ABLC): a molecular rationale for the attenuation of amphotericin B-related toxicities. J Liposome Res. 1993;3:451–72.

    CAS  Google Scholar 

  55. Olsen SJ, Swerdel MR, Blue B, Clark JM, Bonner DP. Tissue distribution of amphotericin B lipid complex in laboratory animals. J Pharm Pharmacol. 1991;43(12):831–5.

    PubMed  CAS  Google Scholar 

  56. Clark JM, Whitney RR, Olsen SJ, George RJ, Swerdel MR, Kunselman L, et al. Amphotericin B lipid complex therapy of experimental fungal infections in mice. Antimicrob Agents Chemother. 1991;35(4):615–21.

    PubMed Central  PubMed  CAS  Google Scholar 

  57. Lee J, Allende M, Dollenberg H, Garrett K, Berenguer J, Francesconi A, et al. Reticuloendothelial loading with amphotericin B lipid complex (ABLC)—a novel pharmacodynamic approach to treatment of experimental hepatosplenic candidiasis (HSC) [abstract no. 172]. In: Interscience conference on antimicrobial agents and chemotherapy (ICAAC), 1992. Anaheim: American Society for Microbiology; 1992. p. 139.

  58. Kan VL, Bennett JE, Amantea MA, Smolskis MC, McManus E, Grasela DM, et al. Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers. J Infect Dis. 1991;164(2):418–21.

    PubMed  CAS  Google Scholar 

  59. Fielding RM, Smith PC, Wang LH, Porter J, Guo LS. Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats. Antimicrob Agents Chemother. 1991;35(6):1208–13.

    PubMed Central  PubMed  CAS  Google Scholar 

  60. Fielding RM, Singer AW, Wang LH, Babbar S, Guo LS. Relationship of pharmacokinetics and drug distribution in tissue to increased safety of amphotericin B colloidal dispersion in dogs. Antimicrob Agents Chemother. 1992;36(2):299–307.

    PubMed Central  PubMed  CAS  Google Scholar 

  61. Fielding RM, Porter J, Jekot J, Guo LSS. Altered tissue distribution results in the reduced toxicity of amphotericin B colloidal dispersion [abstract no. A77]. Annual Meeting of the American Society for Microbiology (ASM), 1991. Dallas: American Society for Microbiology; 1991. p. 13.

  62. Oppenheim BA, Herbrecht R, Kusne S. The safety and efficacy of amphotericin B colloidal dispersion in the treatment of invasive mycoses. Clin Infect Dis. 1995;21(5):1145–53.

    PubMed  CAS  Google Scholar 

  63. Proffitt RT, Satorius A, Chiang SM, Sullivan L, Adler-Moore JP. Pharmacology and toxicology of a liposomal formulation of amphotericin B (AmBisome) in rodents. J Antimicrob Chemother. 1991;28(Suppl B):49–61.

    Google Scholar 

  64. Lee JW, Amantea MA, Francis PA, Navarro EE, Bacher J, Pizzo PA, et al. Pharmacokinetics and safety of a unilamellar liposomal formulation of amphotericin B (AmBisome) in rabbits. Antimicrob Agents Chemother. 1994;38(4):713–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  65. Adler-Moore JP, Proffitt RT. Development, characterization, efficacy and mode of action of AmBisome, a unilamellar liposomal formulation of amphotericin B. J Liposome Res. 1993;3:429–50.

    CAS  Google Scholar 

  66. Ringdén O, Meunier F, Tollemar J, et al. Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother. 1991;28(suppl B):73–82.

    PubMed  Google Scholar 

  67. Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother. 2001;45(12):3487–96.

    PubMed Central  PubMed  CAS  Google Scholar 

  68. Hong Y, Shaw PJ, Nath CE, Yadav SP, Stephen KR, Earl JW, et al. Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother. 2006;50(3):935–42.

    PubMed Central  PubMed  CAS  Google Scholar 

  69. Starke JR, Mason EO Jr, Kramer WG, Kaplan SL. Pharmacokinetics of amphotericin B in infants and children. J Infect Dis. 1987;155(4):766–74.

    PubMed  CAS  Google Scholar 

  70. Wurthwein G, Groll AH, Hempel G, Adler-Shohet FC, Lieberman JM, Walsh TJ. Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother. 2005;49(12):5092–8.

    PubMed Central  PubMed  Google Scholar 

  71. Luna B, Drew RH, Perfect JR. Agents for treatment of invasive fungal infections. Otolaryngol Clin North Am. 2000;33(2):277–99.

    PubMed  CAS  Google Scholar 

  72. Wiederhold NP, Tam VH, Chi J, Prince RA, Kontoyiannis DP, Lewis RE. Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2006;50(2):469–73.

    PubMed Central  PubMed  CAS  Google Scholar 

  73. Speich R, Dutly A, Naef R, Russi EW, Weder W, Boehler A. Tolerability, safety and efficacy of conventional amphotericin B administered by 24-hour infusion to lung transplant recipients. Swiss Med Wkly. 2002;132(31–32):455–8.

    PubMed  CAS  Google Scholar 

  74. Maharom P, Thamlikitkul V. Implementation of clinical practice policy on the continuous intravenous administration of amphotericin B deoxycholate. J Med Assoc Thai. 2006;89(Suppl 5):S118–24.

    PubMed  Google Scholar 

  75. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44(10):1289–97.

    PubMed  CAS  Google Scholar 

  76. Summers KK, Hardin TC, Gore SJ, Graybill JR. Therapeutic drug monitoring of systemic antifungal therapy. J Antimicrob Chemother. 1997;40(6):753–64.

    PubMed  CAS  Google Scholar 

  77. Lyman CA, Walsh TJ. Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs. 1992;44(1):9–35.

    PubMed  CAS  Google Scholar 

  78. Laboratory monitoring of antifungal chemotherapy. British Society for Antimicrobial Chemotherapy Working Party. Lancet. 1991;337(8757):1577–1580

    Google Scholar 

  79. Clements JS Jr, Peacock JE Jr. Amphotericin B revisited: reassessment of toxicity. Am J Med. 1990;88(5N):22N–7N.

    PubMed  Google Scholar 

  80. Graybill JR. Is there a correlation between serum antifungal drug concentration and clinical outcome? J Infect. 1994;28(Suppl 1):17–24.

    PubMed  Google Scholar 

  81. Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm. 1993;21(6):735–50.

    PubMed  CAS  Google Scholar 

  82. Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD. Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis. 2006;42(7):938–44.

    PubMed  CAS  Google Scholar 

  83. Pfaller MA, Espinel-Ingroff A, Canton E, Castanheira M, Cuenca-Estrella M, Diekema DJ, et al. Wild-type MIC distributions and epidemiological cutoff values for amphotericin B, flucytosine, and itraconazole and Candida spp. as determined by CLSI broth microdilution. J Clin Microbiol. 2012;50(6):2040–6.

    PubMed Central  PubMed  CAS  Google Scholar 

  84. Steinbach WJ, Perfect JR, Schell WA, Walsh TJ, Benjamin DK Jr. In vitro analyses, animal models, and 60 clinical cases of invasive Aspergillus terreus infection. Antimicrob Agents Chemother. 2004;48(9):3217–25.

    PubMed Central  PubMed  CAS  Google Scholar 

  85. Sanglard D, Ischer F, Parkinson T, Falconer D, Bille J. Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob Agents Chemother. 2003;47(8):2404–12.

    PubMed Central  PubMed  CAS  Google Scholar 

  86. LA Vincent BM, Scherz-Shouval R, Whitesell L, Lindquist S. Fitness trade-offs restrict the evolution of resistance to amphotericin B. PLoS Biol. 2013;11(10):e1001692.

    PubMed Central  PubMed  CAS  Google Scholar 

  87. Lewis RE, Wiederhold NP. The solubility ceiling: a rationale for continuous infusion amphotericin B therapy? Clin Infect Dis. 2003;37(6):871–2.

    PubMed  Google Scholar 

  88. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis. 1998;27(3):603–18.

    PubMed  CAS  Google Scholar 

  89. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73(9):919–34.

    PubMed  CAS  Google Scholar 

  90. Polak A, Grenson M. Evidence for a common transport system for cytosine, adenine and hypoxanthine in Saccharomyces cerevisiae and Candida albicans. Eur J Biochem. 1973;32(2):276–82.

    PubMed  CAS  Google Scholar 

  91. Waldorf AR, Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983;23(1):79–85.

    PubMed Central  PubMed  CAS  Google Scholar 

  92. Diasio RB, Bennett JE, Myers CE. Mode of action of 5-fluorocytosine. Biochem Pharmacol. 1978;27(5):703–7.

    PubMed  CAS  Google Scholar 

  93. Cutler RE, Blair AD, Kelly MR. Flucytosine kinetics in subjects with normal and impaired renal function. Clin Pharmacol Ther. 1978;24(3):333–42.

    PubMed  CAS  Google Scholar 

  94. Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis. 1992;15(6):1003–18.

    PubMed  CAS  Google Scholar 

  95. Bennet JE. Flucytosine. Ann Intern Med. 1977;86(3):319–21.

    PubMed  CAS  Google Scholar 

  96. Block ER, Bennett JE, Livoti LG, Klein WJ Jr, MacGregor RR, Henderson L. Flucytosine and amphotericin B: hemodialysis effects on the plasma concentration and clearance. Studies in man. Ann Intern Med. 1974;80(5):613–7.

    PubMed  CAS  Google Scholar 

  97. Schonebeck J, Polak A, Fernex M, Scholer HJ. Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy. 1973;18(6):321–36.

    PubMed  CAS  Google Scholar 

  98. Muther RS, Bennett WM. Peritoneal clearance of amphotericin B and 5-fluorocytosine. West J Med. 1980;133(2):157–60.

    PubMed Central  PubMed  CAS  Google Scholar 

  99. Zaoutis TE, Benjamin DK, Steinbach WJ. Antifungal treatment in pediatric patients. Drug Resist Updat. 2005;8(4):235–45.

    PubMed  CAS  Google Scholar 

  100. Vermes A, van Der Sijs H, Guchelaar HJ. Flucytosine: correlation between toxicity and pharmacokinetic parameters. Chemotherapy. 2000;46(2):86–94.

    PubMed  CAS  Google Scholar 

  101. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12(6):1147–201.

    PubMed  CAS  Google Scholar 

  102. Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita VT. Aspergillosis. The spectrum of the disease in 98 patients. Medicine (Baltimore). 1970;49(2):147–73.

    CAS  Google Scholar 

  103. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46(2):171–9.

    PubMed  CAS  Google Scholar 

  104. Warnock DW. Amphotericin B: an introduction. J Antimicrob Chemother. 1991;28(Suppl B):27–38.

    PubMed  CAS  Google Scholar 

  105. Utz JP, Tynes BS, Shadomy HJ, Duma RJ, Kannan MM, Mason KN. 5-Fluorocytosine in human cryptococcosis. Antimicrob Agents Chemother. 1968;8:344–6.

    PubMed  CAS  Google Scholar 

  106. Medoff G, Comfort M, Kobayashi GS. Synergistic action of amphotericin B and 5-fluorocytosine against yeast-like organisms. Proc Soc Exp Biol Med. 1971;138(2):571–4.

    PubMed  CAS  Google Scholar 

  107. Soltani M, Tobin CM, Bowker KE, Sunderland J, MacGowan AP, Lovering AM. Evidence of excessive concentrations of 5-flucytosine in children aged below 12 years: a 12-year review of serum concentrations from a UK clinical assay reference laboratory. Int J Antimicrob Agents. 2006;28(6):574–7.

    PubMed  CAS  Google Scholar 

  108. Hope WW, Warn PA, Sharp A, Reed P, Keevil B, Louie A, et al. Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing. Antimicrob Agents Chemother. 2007;51(10):3760–2.

    PubMed Central  PubMed  CAS  Google Scholar 

  109. Song JC, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig Drugs. 2005;6(2):170–7.

    PubMed  Google Scholar 

  110. Stamm AM, Diasio RB, Dismukes WE, Shadomy S, Cloud GA, Bowles CA, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med. 1987;83(2):236–42.

    PubMed  CAS  Google Scholar 

  111. Benson JM, Nahata MC. Clinical use of systemic antifungal agents. Clin Pharm. 1988;7(6):424–38.

    PubMed  CAS  Google Scholar 

  112. Patel R. Antifungal agents. Part I. Amphotericin B preparations and flucytosine. Mayo Clin Proc. 1998;73(12):1205–25.

    PubMed  CAS  Google Scholar 

  113. Fasoli M, Kerridge D. Isolation and characterization of fluoropyrimidine-resistant mutants in two Candida species. Ann N Y Acad Sci. 1988;544:260–3.

    PubMed  CAS  Google Scholar 

  114. Polak A. 5-Fluorocytosine—current status with special references to mode of action and drug resistance. Contrib Microbiol Immunol. 1977;4:158–67.

    PubMed  CAS  Google Scholar 

  115. Medoff G, Kobayashi GS. Strategies in the treatment of systemic fungal infections. N Engl J Med. 1980;302(3):145–55.

    PubMed  CAS  Google Scholar 

  116. Armstrong D, Schmitt HJ. Older drugs. In: Ryley JF, editor. Chemotherapy for fungal diseases. Berlin: Springer; 1990. p. 439–54.

    Google Scholar 

  117. Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86(8):805–17.

    PubMed Central  PubMed  CAS  Google Scholar 

  118. Odds FC, Brown AJ, Gow NA. Antifungal agents: mechanisms of action. Trends Microbiol. 2003;11(6):272–9.

    PubMed  CAS  Google Scholar 

  119. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12(1):40–79.

    PubMed Central  PubMed  CAS  Google Scholar 

  120. Chen SC, Sorrell TC. Antifungal agents. Med J Aust. 2007;187(7):404–9.

    PubMed  Google Scholar 

  121. Katragkou A, Tsikopoulou F, Roilides E, Zaoutis TE. Posaconazole: when and how? The clinician’s view. Mycoses. 2012;55(2):110–22.

    PubMed  CAS  Google Scholar 

  122. Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother. 2002;46(5):1581–2.

    PubMed Central  PubMed  CAS  Google Scholar 

  123. Arndt CA, Walsh TJ, McCully CL, Balis FM, Pizzo PA, Poplack DG. Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis. 1988;157(1):178–80.

    PubMed  CAS  Google Scholar 

  124. Brammer KW, Tarbit MH. A review of the pharmacokinetics of fluconazole (UK-49,858) in laboratory animals and man. In: Fromtling RA, editor. Recent trends in the discovery, development and evaluation of antifungal agents. Barcelona: JR Prous Science Publishers SA; 1987. p. 141–50.

    Google Scholar 

  125. Farrow PR, Faulkner JK, Brammer KW. The pharmacokinetics of fluconazole [abstract no. 14-199]. Symposium on Fluconazole: a Novel Advance in Therapy for Systemic Fungal Infections; 8–9 Oct 1988; Dorado, Puerto Rico.

  126. Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH. The disposition and metabolism of [14C]fluconazole in humans. Drug Metab Dispos. 1991;19(4):764–7.

    PubMed  CAS  Google Scholar 

  127. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis. 1994;13(4):325–9.

    PubMed  CAS  Google Scholar 

  128. Blum RA, D’Andrea DT, Florentino BM, Wilton JH, Hilligoss DM, Gardner MJ, et al. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med. 1991;114(9):755–7.

    PubMed  CAS  Google Scholar 

  129. Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs. 1990;39(6):877–916.

    PubMed  CAS  Google Scholar 

  130. Saxen H, Hoppu K, Pohjavuori M. Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life. Clin Pharmacol Ther. 1993;54(3):269–77.

    PubMed  CAS  Google Scholar 

  131. De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001;61(Suppl 1):27–37.

    PubMed  Google Scholar 

  132. Boogaerts M, Maertens J. Clinical experience with itraconazole in systemic fungal infections. Drugs. 2001;61(Suppl 1):39–47.

    PubMed  CAS  Google Scholar 

  133. Lange D, Pavao JH, Wu J, Klausner M. Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol. 1997;37(6):535–40.

    PubMed  CAS  Google Scholar 

  134. Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet. 1998;35(6):461–73.

    PubMed  CAS  Google Scholar 

  135. Groll AH, Wood L, Roden M, Mickiene D, Chiou CC, Townley E, et al. Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. Antimicrob Agents Chemother. 2002;46(8):2554–63.

    PubMed Central  PubMed  CAS  Google Scholar 

  136. Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, Lavrijsen K, et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses. 1989;32(Suppl 1):67–87.

    PubMed  Google Scholar 

  137. Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi MG, Kuhn JG. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother. 1988;32(9):1310–3.

    PubMed Central  PubMed  CAS  Google Scholar 

  138. de Repentigny L, Ratelle J, Leclerc JM, Cornu G, Sokal EM, Jacqmin P, et al. Repeated-dose pharmacokinetics of an oral solution of itraconazole in infants and children. Antimicrob Agents Chemother. 1998;42(2):404–8.

    PubMed Central  PubMed  Google Scholar 

  139. Abdel-Rahman SM, Jacobs RF, Massarella J, Kauffman RE, Bradley JS, Kimko HC, et al. Single-dose pharmacokinetics of intravenous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents. Antimicrob Agents Chemother. 2007;51(8):2668–73.

    PubMed Central  PubMed  CAS  Google Scholar 

  140. Prentice AG, Warnock DW, Johnson SA, Phillips MJ, Oliver DA. Multiple dose pharmacokinetics of an oral solution of itraconazole in autologous bone marrow transplant recipients. J Antimicrob Chemother. 1994;34(2):247–52.

    PubMed  CAS  Google Scholar 

  141. Prentice AG, Warnock DW, Johnson SA, Taylor PC, Oliver DA. Multiple dose pharmacokinetics of an oral solution of itraconazole in patients receiving chemotherapy for acute myeloid leukaemia. J Antimicrob Chemother. 1995;36(4):657–63.

    PubMed  CAS  Google Scholar 

  142. Quinney SK, Galinsky RE, Jiyamapa-Serna VA, Chen Y, Hamman MA, Hall SD, et al. Hydroxyitraconazole, formed during intestinal first-pass metabolism of itraconazole, controls the time course of hepatic CYP3A inhibition and the bioavailability of itraconazole in rats. Drug Metab Dispos. 2008;36(6):1097–101.

    PubMed  CAS  Google Scholar 

  143. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother. 2009;53(1):24–34.

    PubMed Central  PubMed  CAS  Google Scholar 

  144. Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol. 2002;42(4):395–402.

    PubMed  CAS  Google Scholar 

  145. Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver SD. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol. 2003;56(Suppl 1):10–6.

    PubMed Central  PubMed  CAS  Google Scholar 

  146. Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother. 2002;46(8):2546–53.

    PubMed Central  PubMed  CAS  Google Scholar 

  147. Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos. 2003;31(5):540–7.

    PubMed  CAS  Google Scholar 

  148. Service RF. Pharmacogenomics. Going from genome to pill. Science. 2005;308(5730):1858–60.

    PubMed  CAS  Google Scholar 

  149. Friberg LE, Ravva P, Karlsson MO, Liu P. Integrated population pharmacokinetic analysis of voriconazole in children, adolescents, and adults. Antimicrob Agents Chemother. 2012;56(6):3032–42.

    PubMed Central  PubMed  CAS  Google Scholar 

  150. Hope WW. Population pharmacokinetics of voriconazole in adults. Antimicrob Agents Chemother. 2012;56(1):526–31.

    PubMed Central  PubMed  CAS  Google Scholar 

  151. Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M. Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther. 2004;75(6):587–8.

    PubMed  CAS  Google Scholar 

  152. Walsh TJ, Karlsson MO, Driscoll T, Arguedas AG, Adamson P, Saez-Llorens X, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother. 2004;48(6):2166–72.

    PubMed Central  PubMed  CAS  Google Scholar 

  153. Michael C, Bierbach U, Frenzel K, Lange T, Basara N, Niederwieser D, et al. Voriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients. Antimicrob Agents Chemother. 2010;54(8):3225–32.

    PubMed Central  PubMed  CAS  Google Scholar 

  154. Pasqualotto AC, Shah M, Wynn R, Denning DW. Voriconazole plasma monitoring. Arch Dis Child. 2008;93(7):578–81.

    PubMed  CAS  Google Scholar 

  155. Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010;50(1):27–36.

    PubMed Central  PubMed  CAS  Google Scholar 

  156. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201–11.

    PubMed  CAS  Google Scholar 

  157. Choi SH, Lee SY, Hwang JY, Lee SH, Yoo KH, Sung KW, et al. Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer. 2013;60(1):82–7.

    PubMed  Google Scholar 

  158. Lipp HP. Clinical pharmacodynamics and pharmacokinetics of the antifungal extended-spectrum triazole posaconazole: an overview. Br J Clin Pharmacol. 2010;70(4):471–80.

    PubMed Central  PubMed  CAS  Google Scholar 

  159. Moxafil® [package insert]. Whitehouse Station: Merck & Co., Inc.; 2013.

  160. Krishna G, AbuTarif M, Xuan F, Martinho M, Angulo D, Cornely OA. Pharmacokinetics of oral posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Pharmacotherapy. 2008;28(10):1223–32.

    PubMed  CAS  Google Scholar 

  161. Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother. 2003;47(9):2788–95.

    PubMed Central  PubMed  CAS  Google Scholar 

  162. Ezzet F, Wexler D, Courtney R, Krishna G, Lim J, Laughlin M. Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations. Clin Pharmacokinet. 2005;44(2):211–20.

    PubMed  CAS  Google Scholar 

  163. Krishna G, Ma L, Martinho M, Preston RA, O’Mara E. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother. 2012;67(11):2725–30.

    PubMed Central  PubMed  CAS  Google Scholar 

  164. Krishna G, Ma L, Martinho M, O’Mara E. Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother. 2012;56(8):4196–201.

    PubMed Central  PubMed  CAS  Google Scholar 

  165. Wexler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M. Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study. Eur J Pharm Sci. 2004;21(5):645–53.

    PubMed  CAS  Google Scholar 

  166. Galetin A, Hinton LK, Burt H, Obach RS, Houston JB. Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug–drug interactions for CYP3A4 cleared drugs. Curr Drug Metab. 2007;8(7):685–93.

    PubMed  CAS  Google Scholar 

  167. Conte JE Jr, Golden JA, Krishna G, McIver M, Little E, Zurlinden E. Intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole at steady state in healthy subjects. Antimicrob Agents Chemother. 2009;53(2):703–7.

    PubMed Central  PubMed  CAS  Google Scholar 

  168. Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, et al. Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos. 2004;32(2):267–71.

    PubMed  CAS  Google Scholar 

  169. Schiller DS, Fung HB. Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007;29(9):1862–86.

    PubMed  CAS  Google Scholar 

  170. Krishna G, Sansone-Parsons A, Martinho M, Kantesaria B, Pedicone L. Posaconazole plasma concentrations in juvenile patients with invasive fungal infection. Antimicrob Agents Chemother. 2007;51(3):812–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  171. Lee JW, Seibel NL, Amantea M, Whitcomb P, Pizzo PA, Walsh TJ. Safety and pharmacokinetics of fluconazole in children with neoplastic diseases. J Pediatr. 1992;120(6):987–93.

    PubMed  CAS  Google Scholar 

  172. Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwenbergh G. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol. 1989;36(4):423–6.

    PubMed  Google Scholar 

  173. Tapaninen T, Backman JT, Kurkinen KJ, Neuvonen PJ, Niemi M. Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. J Clin Pharmacol. 2011;51(3):359–67.

    PubMed  CAS  Google Scholar 

  174. Hall SD, Thummel KE, Watkins PB, Lown KS, Benet LZ, Paine MF, et al. Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos. 1999;27(2):161–6.

    PubMed  CAS  Google Scholar 

  175. Bartell APA, Horn K, Postelnick M. Drug interactions involving antifungal drugs: time course and clinical significance. Curr Fungal Infect Rep. 2010;4:103–10.

    Google Scholar 

  176. Doby EH, Benjamin DK Jr, Blaschke AJ, Ward RM, Pavia AT, Martin PL, et al. Therapeutic monitoring of voriconazole in children less than three years of age: a case report and summary of voriconazole concentrations for ten children. Pediatr Infect Dis J. 2012;31(6):632–5.

    PubMed Central  PubMed  Google Scholar 

  177. Burgos A, Zaoutis TE, Dvorak CC, Hoffman JA, Knapp KM, Nania JJ, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121(5):e1286–94.

    PubMed  Google Scholar 

  178. Spriet I, Cosaert K, Renard M, Uyttebroeck A, Meyts I, Proesmans M, et al. Voriconazole plasma levels in children are highly variable. Eur J Clin Microbiol Infect Dis. 2011;30(2):283–7.

    PubMed  CAS  Google Scholar 

  179. Shima H, Miharu M, Osumi T, Takahashi T, Shimada H. Differences in voriconazole trough plasma concentrations per oral dosages between children younger and older than 3 years of age. Pediatr Blood Cancer. 2010;54(7):1050–2.

    PubMed  Google Scholar 

  180. Bartelink IH, Wolfs T, Jonker M, de Waal M, Egberts TC, Ververs TT, et al. Highly variable plasma concentrations of voriconazole in pediatric hematopoietic stem cell transplantation patients. Antimicrob Agents Chemother. 2013;57(1):235–40.

    PubMed Central  PubMed  CAS  Google Scholar 

  181. Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother. 2009;53(3):935–44.

    PubMed Central  PubMed  CAS  Google Scholar 

  182. Maples HD, Stowe CD, Saccente SL, Jacobs RF. Voriconazole serum concentrations in an infant treated for Trichosporon beigelii infection. Pediatr Infect Dis J. 2003;22(11):1022–4.

    PubMed  Google Scholar 

  183. Gubbins PO, Krishna G, Sansone-Parsons A, Penzak SR, Dong L, Martinho M, et al. Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients. Antimicrob Agents Chemother. 2006;50(6):1993–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  184. Anaissie EJ, Bodey GP, Rinaldi MG. Emerging fungal pathogens. Eur J Clin Microbiol Infect Dis. 1989;8(4):323–30.

    PubMed  CAS  Google Scholar 

  185. Anaissie EJ, Kontoyiannis DP, Huls C, Vartivarian SE, Karl C, Prince RA, et al. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J Infect Dis. 1995;172(2):599–602.

    PubMed  CAS  Google Scholar 

  186. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE, et al. Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin infect Dis. 2000;30(4):662–78.

    PubMed  CAS  Google Scholar 

  187. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.

    PubMed  CAS  Google Scholar 

  188. Piper L, Smith PB, Hornik CP, Cheifetz IM, Barrett JS, Moorthy G, et al. Fluconazole loading dose pharmacokinetics and safety in infants. Pediatr Infect Dis J. 2011;30(5):375–8.

    PubMed Central  PubMed  Google Scholar 

  189. Pfaller MA, Diekema DJ, Rex JH, Espinel-Ingroff A, Johnson EM, Andes D, et al. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol. 2006;44(3):819–26.

    PubMed Central  PubMed  CAS  Google Scholar 

  190. Food and Drug Administration. Briefing document for voriconazole. United States Food and Drug Administration, Washington DC. 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2.htm. Accessed 24 Nov 2013.

  191. Soler-Palacin P, Frick MA, Martin-Nalda A, Lanaspa M, Pou L, Rosello E, et al. Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study. J Antimicrob Chemother. 2012;67(3):700–6.

    PubMed  CAS  Google Scholar 

  192. Andes D, Marchillo K, Conklin R, Krishna G, Ezzet F, Cacciapuoti A, et al. Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Antimicrob Agents Chemother. 2004;48(1):137–42.

    PubMed Central  PubMed  CAS  Google Scholar 

  193. Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44(1):2–12.

    PubMed  CAS  Google Scholar 

  194. Pfaller MA, Diekema DJ, Sheehan DJ. Interpretive breakpoints for fluconazole and Candida revisited: a blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev. 2006;19(2):435–47.

    PubMed Central  PubMed  CAS  Google Scholar 

  195. Wade KC, Benjamin DK Jr, Kaufman DA, Ward RM, Smith PB, Jayaraman B, et al. Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants. Pediatr Infect Dis J. 2009;28(8):717–23.

    PubMed Central  PubMed  Google Scholar 

  196. Andes D. Pharmacokinetics and pharmacodynamics of antifungals. Infect Dis Clin North Am. 2006;20(3):679–97.

    PubMed  Google Scholar 

  197. Berenguer J, Ali NM, Allende MC, Lee J, Garrett K, Battaglia S, et al. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother. 1994;38(6):1303–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  198. Cartledge JD, Midgely J, Gazzard BG. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis. J Clin Pathol. 1997;50(6):477–80.

    PubMed Central  PubMed  CAS  Google Scholar 

  199. Denning DW, Tucker RM, Hanson LH, Stevens DA. Treatment of invasive aspergillosis with itraconazole. Am J Med. 1989;86(6 Pt 2):791–800.

    PubMed  CAS  Google Scholar 

  200. Tucker RM, Denning DW, Arathoon EG, Rinaldi MG, Stevens DA. Itraconazole therapy for nonmeningeal coccidioidomycosis: clinical and laboratory observations. J Am Acad Dermatol. 1990;23(3 Pt 2):593–601.

    PubMed  CAS  Google Scholar 

  201. Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med. 1989;149(10):2301–8.

    PubMed  CAS  Google Scholar 

  202. Andes D. Optimizing antifungal choice and administration. Curr Med Res Opin. 2013;29(Suppl 4):13–8.

    PubMed  CAS  Google Scholar 

  203. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335–47.

    PubMed  CAS  Google Scholar 

  204. Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C, et al. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. Clin Infect Dis. 2006;42(12):1726–34.

    PubMed  CAS  Google Scholar 

  205. Bruggemann RJ, Alffenaar JW, Blijlevens NM, Billaud EM, Kosterink JG, Verweij PE, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48(10):1441–58.

    PubMed  Google Scholar 

  206. Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Saral R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med. 1991;325(18):1274–7.

    PubMed  CAS  Google Scholar 

  207. Collin B, Clancy CJ, Nguyen MH. Antifungal resistance in non-albicans Candida species. Drug Resist Updat. 1999;2(1):9–14.

    PubMed  Google Scholar 

  208. Enwuru CA, Ogunledun A, Idika N, Enwuru NV, Ogbonna F, Aniedobe M, et al. Fluconazole resistant opportunistic oro-pharyngeal Candida and non-Candida yeast-like isolates from HIV infected patients attending ARV clinics in Lagos, Nigeria. Afr Health Sci. 2008;8(3):142–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  209. Millon L. Fluconazole-resistant recurrent oral candidiasis in human immunodeficiency virus positive patients: persistence of Candida albicans strains with the same genotype. J Clin Microbiol. 1992;32(4):1115–8.

    Google Scholar 

  210. Mann PA, McNicholas PM, Chau AS, Patel R, Mendrick C, Ullmann AJ, et al. Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species. Antimicrob Agents Chemother. 2009;53(12):5026–34.

    PubMed Central  PubMed  CAS  Google Scholar 

  211. Li X, Brown N, Chau AS, Lopez-Ribot JL, Ruesga MT, Quindos G, et al. Changes in susceptibility to posaconazole in clinical isolates of Candida albicans. J Antimicrob Chemother. 2004;53(1):74–80.

    PubMed  CAS  Google Scholar 

  212. Hof H. A new, broad-spectrum azole antifungal: posaconazole—mechanisms of action and resistance, spectrum of activity. Mycoses. 2006;49(Suppl 1):2–6.

    PubMed  CAS  Google Scholar 

  213. Verweij PE, Mellado E, Melchers WJ. Multiple-triazole-resistant aspergillosis. N Engl J Med. 2007;356(14):1481–3.

    PubMed  CAS  Google Scholar 

  214. Diaz-Guerra TM, Mellado E, Cuenca-Estrella M, Rodriguez-Tudela JL. A point mutation in the 14alpha-sterol demethylase gene cyp51A contributes to itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2003;47(3):1120–4.

    PubMed Central  PubMed  CAS  Google Scholar 

  215. van der Linden JW, Camps SM, Kampinga GA, Arends JP, Debets-Ossenkopp YJ, Haas PJ, et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis. 2013;57(4):513–20.

    PubMed  Google Scholar 

  216. Nivoix Y, Velten M, Letscher-Bru V, Moghaddam A, Natarajan-Ame S, Fohrer C, et al. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis. 2008;47(9):1176–84.

    PubMed  Google Scholar 

  217. Denning DW, Bowyer P. Voriconazole resistance in Aspergillus fumigatus: should we be concerned? Clin Infect Dis. 2013;57(4):521–3.

    PubMed  CAS  Google Scholar 

  218. Guembe M, Guinea J, Pelaez T, Torres-Narbona M, Bouza E. Synergistic effect of posaconazole and caspofungin against clinical zygomycetes. Antimicrob Agents Chemother. 2007;51(9):3457–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  219. Seyedmousavi S, Bruggemann RJ, Melchers WJ, Rijs AJ, Verweij PE, Mouton JW. Efficacy and pharmacodynamics of voriconazole combined with anidulafungin in azole-resistant invasive aspergillosis. J Antimicrob Chemother. 2013;68(2):385–93.

    PubMed  CAS  Google Scholar 

  220. Prasad PA, Coffin SE, Leckerman KH, Walsh TJ, Zaoutis TE. Pediatric antifungal utilization: new drugs, new trends. Pediatr Infect Dis J. 2008;27(12):1083–8.

    PubMed  Google Scholar 

  221. Hoffman JA, Walsh TJ. Echinocandins in children. Pediatr Infect Dis J. 2011;30(6):508–9.

    PubMed  Google Scholar 

  222. Astellas Pharma US, Inc. FDA approves pediatric indication for Astellas’ MYCAMINE® (micafungin sodium) for injection. 2013. http://www.astellas.us/docs/mycamine.pdf. Accessed 27 Nov 2013.

  223. Larru B, Zaoutis TE. Newer antifungal agents. Curr Opin Pediatr. 2013;25(1):110–5.

    PubMed  CAS  Google Scholar 

  224. Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs. 2011;71(1):11–41.

    PubMed  CAS  Google Scholar 

  225. Simitsopoulou M, Peshkova P, Tasina E, Katragkou A, Kyrpitzi D, Velegraki A, et al. Species-specific and drug-specific differences in susceptibility of Candida biofilms to echinocandins: characterization of less common bloodstream isolates. Antimicrob Agents Chemother. 2013;57(6):2562–70.

    PubMed Central  PubMed  CAS  Google Scholar 

  226. Pieroni KP, Nespor C, Poole RL, Kerner JA Jr, Berquist WE. Echinocandin and ethanol lock therapy treatment of fungal catheter infections. Pediatr Infect Dis J. 2013;32(3):289–91.

    PubMed  Google Scholar 

  227. Stone JA, Xu X, Winchell GA, Deutsch PJ, Pearson PG, Migoya EM, et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother. 2004;48(3):815–23.

    PubMed Central  PubMed  CAS  Google Scholar 

  228. Undre NA, Stevenson P, Freire A, Arrieta A. Pharmacokinetics of micafungin in pediatric patients with invasive candidiasis and candidemia. Pediatr Infect Dis J. 2012;31(6):630–2.

    PubMed  Google Scholar 

  229. Benjamin DK Jr, Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother. 2006;50(2):632–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  230. Pound MW, Townsend ML, Drew RH. Echinocandin pharmacodynamics: review and clinical implications. J Antimicrob Chemother. 2010;65(6):1108–18.

    PubMed  CAS  Google Scholar 

  231. Moriyama B, Henning SA, Penzak SR, Walsh TJ. The postantifungal and paradoxical effects of echinocandins against Candida spp. Future Microbiol. 2012;7(5):565–9.

    PubMed  CAS  Google Scholar 

  232. Steinbach WJ, Roilides E, Berman D, Hoffman JA, Groll AH, Bin-Hussain I, et al. Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates. Pediatr Infect Dis J. 2012;31(12):1252–7.

    PubMed  Google Scholar 

  233. Queiroz-Telles F, Berezin E, Leverger G, Freire A, van der Vyver A, Chotpitayasunondh T, et al. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. Pediatr Infect Dis J. 2008;27(9):820–6.

    PubMed  Google Scholar 

  234. Undre N, Stevenson P, Baraldi E. Pharmacokinetics of micafungin in HIV positive patients with confirmed esophageal candidiasis. Eur J Drug Metab Pharmacokinet. 2012;37(1):31–8.

    PubMed  CAS  Google Scholar 

  235. Zhao W, Hope WW, Manzoni P, Jacqz-Aigrain E. Optimizing micafungin dosing in children. The Pediatric infectious disease journal. 2012;31(11):1211–2; author reply 1212.

  236. Benjamin DK Jr, Smith PB, Arrieta A, Castro L, Sanchez PJ, Kaufman D, et al. Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin Pharmacol Ther. 2010;87(1):93–9.

    PubMed Central  PubMed  Google Scholar 

  237. Watt KM, Cohen-Wolkowiez M, Ward RM, Benjamin DK Jr. Commentary: pediatric antifungal drug development: lessons learned and recommendations for the future. Pediatr Infect Dis J. 2012;31(6):635–7.

    PubMed Central  PubMed  Google Scholar 

  238. Tapisiz A. Anidulafungin: is it a promising option in the treatment of pediatric invasive fungal infections? Expert Rev Anti infect Ther. 2011;9(3):339–46.

    PubMed  CAS  Google Scholar 

  239. Wilke MH. Invasive fungal infections in infants-focus on anidulafungin. Clin Med Insights Pediatr. 2013;7:7–11.

    PubMed Central  PubMed  Google Scholar 

  240. Goodwin ML, Drew RH. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother. 2008;61(1):17–25.

    PubMed  CAS  Google Scholar 

  241. Jans J, Bruggemann RJ, Christmann V, Verweij PE, Warris A. Favorable outcome of neonatal cerebrospinal fluid shunt-associated Candida meningitis with caspofungin. Antimicrob Agents Chemother. 2013;57(5):2391–3.

    PubMed Central  PubMed  CAS  Google Scholar 

  242. Kartsonis NA, Nielsen J, Douglas CM. Caspofungin: the first in a new class of antifungal agents. Drug Resist Updat. 2003;6(4):197–218.

    PubMed  CAS  Google Scholar 

  243. Hebert MF, Townsend RW, Austin S, Balan G, Blough DK, Buell D, et al. Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol. 2005;45(8):954–60.

    PubMed  CAS  Google Scholar 

  244. Saner F, Gensicke J, Rath P, Fruhauf N, Gu Y, Paul A, et al. Safety profile of concomitant use of caspofungin and cyclosporine or tacrolimus in liver transplant patients. Infection. 2006;34(6):328–32.

    PubMed  CAS  Google Scholar 

  245. Pfaller MA, Messer SA, Woosley LN, Jones RN, Castanheira M. Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol. 2013;51(8):2571–81.

    PubMed Central  PubMed  CAS  Google Scholar 

  246. Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag. 2007;3(1):71–97.

    PubMed Central  PubMed  CAS  Google Scholar 

  247. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, et al. Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat. 2011;14(3):164–76.

    PubMed  CAS  Google Scholar 

  248. Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol. 2012;50(4):1199–203.

    PubMed Central  PubMed  CAS  Google Scholar 

  249. Alexander BD, Johnson MD, Pfeiffer CD, Jimenez-Ortigosa C, Catania J, Booker R, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56(12):1724–32.

    PubMed  Google Scholar 

  250. Mori M. Nationwide survey of treatment for pediatric patients with invasive fungal infections in Japan. J Infect Chemother. 2013;19(5):946–50.

    PubMed Central  PubMed  CAS  Google Scholar 

  251. Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis. 1996;22(Suppl 2):S133–44.

    PubMed  CAS  Google Scholar 

  252. Groll AH, Giri N, Petraitis V, Petraitiene R, Candelario M, Bacher JS, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis. 2000;182(1):274–82.

    PubMed  CAS  Google Scholar 

  253. Groll AH, Lyman CA, Petraitis V, Petraitiene R, Armstrong D, Mickiene D, et al. Compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations. Antimicrob Agents Chemother. 2006;50(10):3418–23.

    PubMed Central  PubMed  CAS  Google Scholar 

  254. Hoesley C, Dismumkes WE. Overview of oral azole drugs as systemic antifungal therapy. Semin Respir Crit Care Med. 1997;18(3):301–9.

    Google Scholar 

  255. Dismukes WE. Introduction to antifungal drugs. Clin Infect Dis. 2000;30(4):653–7.

    PubMed  CAS  Google Scholar 

  256. Katz HI. Drug interactions of the newer oral antifungal agents. Br J Dermatol. 1999;141(Suppl 56):26–32.

    PubMed  Google Scholar 

  257. Lexi-Comp. Drug interactions handbook, and drug interactions software. http://www.lexi.com/institutions/products/pda/lexi-drugs-lexi-interact/. Accessed 23 Nov 2013.

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Acknowledgments

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Funding

This work was supported by grants from the US National Institute of Allergy and Infectious Diseases [Grant Number U01A1082482] (to KA) and the Centres for Disease Control Prevention [U18-IP000303-01] (to CS, KA).

Transparency Declarations

The authors declare that they have no conflicts of interest.

Contributors

CS, JEC, JKR, MGS and CMTS developed the review and wrote the initial draft of the manuscript. Additionally, all authors contributed substantively to the review and revision of the final version.

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  1. Division of Clinical Pharmacology, Department of Paediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA

    Chris Stockmann, Jonathan E. Constance, Jessica K. Roberts, Michael G. Spigarelli & Catherine M. T. Sherwin

  2. Division of Infectious Diseases, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    Chris Stockmann, Jared Olson, Elizabeth H. Doby & Krow Ampofo

  3. Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    Justin Stiers

  4. Department of Pharmacology/Toxicology, University of Utah College of Pharmacy, Salt Lake City, UT, USA

    Chris Stockmann & Michael G. Spigarelli

  5. Pharmacy, Primary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UT, USA

    Jared Olson

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  1. Chris Stockmann
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Correspondence to Catherine M. T. Sherwin.

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Stockmann, C., Constance, J.E., Roberts, J.K. et al. Pharmacokinetics and Pharmacodynamics of Antifungals in Children and their Clinical Implications. Clin Pharmacokinet 53, 429–454 (2014). https://doi.org/10.1007/s40262-014-0139-0

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Keywords

  • Fluconazole
  • Itraconazole
  • Voriconazole
  • Therapeutic Drug Monitoring
  • Invasive Aspergillosis